Abstract
Purpose :
Photoreceptor degeneration leads to acquired blindness, and it is common in conditions such as retinitis pigmentosa, retinal toxicity, and age-related macular degeneration. Drugs that protect the retina from photoreceptor loss are much needed, as most retinal degenerative diseases have no treatment. We aim to seek effective pharmacological treatments to prevent retinal degeneration using target-based and phenotypic strategies.
Methods :
Lead compounds were identified using small molecule drug screening targeting rhodopsin homeostasis, and one compound was identified from aging studies in other organs. The leads were tested firstly in immortal mammalian stable cells in vitro, and they were then studied using retinal explant culture. Finally, the most efficacious compounds were studied in vivo using systemic or intraocular administrations to rodent models of retinal degeneration (RhoP23H/+ knock-in mice and aged Fischer344 rats). Efficacy and mechanism of actions of compounds were evaluated using combined methods of electroretinogram (ERG), optic coherence tomography (OCT), immunohistochemistry, RNA-seq, and immunoblots.
Results :
Three types of retinal protecting agents were identified: 1) non-retinoid chaperones of rhodopsin; 2) selective inducers of misfolded rhodopsin clearance; and 3) anti-aging purine metabolite against age-related photoreceptor degeneration.
Conclusions :
We showed proof-of-principle evidence that photoreceptor degeneration due to RHO misfolding mutations can be rescued by restoring proteostasis using small molecule chaperones or inducers of misfolded protein clearance. Age-related photoreceptor loss can be rescued by oral administration of an anti-aging purine metabolite.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.